Dying Back or Compartmentalized Axonal Degeneration

One of the most intriguing aspects of the axon biology is that most peripheral neuropathies, clinical or experimental, present as distal axonopathy. In most peripheral neuropathies, and many CNS disorders, distal portions of the axons degenerate, yet the neuronal cell body and the proximal axon are maintained. How does a neuron and/or an axon do this? In wallerian degeneration, the distal segment of a transected axon is separated and compartmentalized from the cell body and the proximal axon. Degeneration of the compartmentalized distal segment can ensue without any harm to the proximal axon or the cell body. However, in the case of distal axonopathies, the distal segment of the axon has to degenerate and at the same time maintain compartmentaliza-tion. The molecular mechanisms of such compartmentaliza-tion and degeneration are unknown, but may differ from the molecular mechanisms used by typical wallerian degeneration (Fig. 4). There are only a handful of experimental studies available to draw any conclusions on this matter. One experimental approach has been to use compartmentalized cell culture techniques where one can separate the neuronal cell body from the axon (Campenot, 1982). Campenot and colleagues (1994) demonstrated that local withdrawal of nerve growth factor from the chamber where the axons are located leads to degeneration of the axons only in that chamber, with no effect on the survival of the neuronal cell body (Campenot, 1994). So far, this culture technique has been used primarily to study the effects of nerve growth factor on axon biology (Riccio et al., 1997; Kuruvilla et al., 2000), but it is possible to use the same technique to study the mechanism of action of various toxic insults to the neuron and/or the axon. Furthermore, by using a co-culture paradigm in the compartmentalized culture system, one can begin to examine the interplay between various cell types in the PNS or CNS. For example, what are the roles of oligodendrocytes in neuronal survival vs. axonal survival? Are they linked to each other? Do microglia play a role in axonal survival? Are activated microglia injurious to the axon independent of their action on the neuronal cell body? These types of questions are difficult to answer using traditional co-culture systems

Transection ■

Wallerian Degeneration

Chronic Injury

Chronic Injury /A

Figure 4 Various forms of axonal degeneration. (A) When an axon is cut, the isolated distal segment rapidly undergoes wallerian degeneration. When the axon of a developing neuron is cut, the cell body frequently undergoes apoptosis. (B) In dying-back axonal degeneration, the axonal tree of an unhealthy neuron slowly degenerates, beginning distally and progressing proximally. (C) When the distal part of an axon of a sympathetic neuron is locally deprived of nerve growth factor in a three-chamber culture dish, the deprived axon segment degenerates, whereas the rest of the axon and the cell survive. (With permission adapted from Raff at. al., 2002.)

Figure 4 Various forms of axonal degeneration. (A) When an axon is cut, the isolated distal segment rapidly undergoes wallerian degeneration. When the axon of a developing neuron is cut, the cell body frequently undergoes apoptosis. (B) In dying-back axonal degeneration, the axonal tree of an unhealthy neuron slowly degenerates, beginning distally and progressing proximally. (C) When the distal part of an axon of a sympathetic neuron is locally deprived of nerve growth factor in a three-chamber culture dish, the deprived axon segment degenerates, whereas the rest of the axon and the cell survive. (With permission adapted from Raff at. al., 2002.)

because one cannot isolate the effects of the intervention on the neuronal cell body from the effects on the axons. What do we know about the role of glial cells in wallerian degeneration? This issue is discussed in the next two sections.

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